1-(4-Hydroxyphenyl)-4-(4-trifluoromethoxyphenoxy)piperidine and salts thereof are compounds that are useful as an intermediate in the synthesis of various pharmaceutical compositions (preferably antitubercular agents), agricultural chemicals, etc.
A method comprising reacting a cyclohexanedione compound and an amine compound under neutral or basic conditions is known as a method for producing 1-(4-hydroxyphenyl)-4-(4-trifluoromethoxyphenoxy)piperidine (Patent Literature (PTL) 1).
Since this method requires oxidizing an intermediate with oxygen to obtain the desired product, an operation of passing air or oxygen through the reaction system is essential. However, the operation of passing air or oxygen through the reaction system requires a special device, as well as complicated steps of supplying an appropriate amount of oxygen in accordance with the progress of the reaction. When oxygen is not present in the reaction system, the reaction progresses only up to the formation of an imine, and thus fails to efficiently obtain the desired product.
Further, to supply oxygen to the reaction system, oxygen must be dissolved in a solvent. Therefore, a certain amount of solvent is necessary for the reaction. Further, to supplement the solvent that decreases mainly due to evaporation by aeration, appropriately adding the solvent is also required. Accordingly, the amount of organic solvent used inevitably becomes large, which is environmentally unfriendly. Furthermore, when this reaction is carried out on a large scale, performing the reaction with good repeatability is difficult. In addition, since the reaction requires heating in the presence of an organic solvent and oxygen for a long time, anti-combustion measures must also be taken.
Further, since the cyclohexanedione compound, used as a reactant, is a compound obtained from the corresponding aromatic compound by adding high-pressure hydrogen, the method disclosed in PTL 1 is not preferable in terms of supplied amount and cost. The desired aminophenol compound, which has an electron-rich aromatic ring, is extremely unstable to oxidizing conditions. Therefore, even if the conditions are highly optimized, the oxidation reaction progresses excessively under oxygen oxidation conditions, and purification of by-products is inevitable, thus requiring a great deal of labor for complicated purification of byproducts, management for preventing oxidation byproducts, etc.
Thus, the method disclosed in PTL 1 has unsolved problems in terms of costs, supplied amount, etc., and is not an industrially preferable method.
As methods for introducing an amino group into an aromatic compound, reaction systems using a metal catalyst or the like are also known. However, such a method is not industrially preferable, because using a metal catalyst increases the number of steps and costs. All such known methods have high production costs, and a more inexpensive production method has been desired for pharmaceutical compositions assumed to be supplied to developing countries, such as antitubercular agents.
Patent Literature (PTL) 2 discloses a method for producing a specific N,N-dialkylaminophenol by reacting a dihydric phenol with a specific secondary amine. However, this method does not produce 1-(4-hydroxyphenyl)-4-(4-trifluoromethoxyphenoxy)piperidine. Furthermore, in order to prevent the reduction of reaction efficiency due to increased basicity of the reaction system, this method requires using a secondary amine in an amount that is more than the amount of dihydric phenol.